1. Field of the Invention
The present invention relates to a thionucleoside derivative or a salt thereof which is useful as a tumor treatment agent and a pharmaceutical composition.
2. Description of the Related Art
It has been known that 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (hereinafter, also referred to as compound A), which is a thionucleoside, has an excellent antitumor action and is useful in the treatment of malignant tumors (for example, lung cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, pancreatic cancer, breast cancer, renal cancer, bladder cancer, uterine cancer, osteosarcoma, and melanoma) and the like (WO1997/038001A).
On the other hand, it has been known that gemcitabine (2′,2′-difluoro-2′-deoxycytidine), which is a nucleoside, is effective against cancerous tumors such as the large intestine, lung, pancreas, breast, bladder and ovarian tumors (Cancer Research, Vol. 50, pp 4417 to 4422, 1990 and Anti-Cancer Drugs, Vol. 6, pp 7 to 13, 1995). Gemcitabine has become a standard chemotherapy of pancreatic cancer after receiving the FDA approval in 1996 and has also recently received an approval for use in the treatment of non-small cell lung cancer, ovarian cancer, bladder cancer, and breast cancer.
In this regard, congenital or acquired resistance to nucleoside analogues (for example, gemcitabine, 5-fluorouracil, cytarabine, and fludarabine) is a common problem in cancer therapy and is considered as an important cause of a low patient survival rate. Like other nucleoside analogues, gemcitabine is also faced with many problems of congenital or acquired drug resistance (Journal of Medicinal Chemistry, Vol. 57, pp 1531 to 1542, 2014). It has been reported that acquisition of the resistance to gemcitabine by tumor cells results in a decreased overall survival time of cancer patients (Neoplasia, Vol. 12, pp 807 to 817, 2010).
To overcome the resistance to gemcitabine, the development of new drugs based on resistance mechanisms has been carried out and for example, a compound obtained by adding an amide phosphite ester to gemcitabine is known (Journal of Medicinal Chemistry, Vol. 57, pp 1531 to 1542, 2014).